Overweight, obesity, and a sedentary lifestyle increase risk for several types of cancer. Currently, little is known about the effects of lifestyle change at the cellular level in humans. The telomeric regions of chromosomes comprise the molecular caps or ends of the chromosomes. Progressive telomere shortening of somatic cells with successive cell division is a hallmark of cellular aging, with loss of ~ 50-100 base pairs per cell division. Recent epidemiologic studies have suggested an association between telomere shortening in peripheral blood cells and increased risk of several cancers. Observational data suggests that overweight and obesity are associated with telomere shortening, but there is a lack of research on 1) the independent and combined effects of dietary weight loss and exercise on telomere length and 2) the amount of weight loss, or change in body composition that may be necessary to effect changes in telomere length. We propose to investigate within a completed randomized trial the independent and combined effects of dietary weight loss, exercise, and the two combined, compared with controls, on leukocyte telomere length (T/S ratio) measured in samples collected at baseline and 12 months in 438 postmenopausal, overweight/obese, sedentary women aged 50-75 years. Women were randomized to reduced calorie weight loss diet-only that achieved a mean 9.9% loss of baseline weight (N=118); 2) moderate intensity aerobic exercise (225 min/wk) intervention exercise-only that produced a mean 2.6% weight loss (N=117); 3) both interventions diet+exercise with mean 11.6% weight loss (N=116); and 4) control (0.7% weight loss) (N=87). The weight loss program was a group-based modification of the Diabetes Prevention Program lifestyle change weight loss program, and included goals of 500-1000 kcal/day reduction, dietary fat < 25% of calories, goal 10% weight loss in first 6 months, and behavioral change techniques. Mean exercise over 12 months was 83% of goal 225 minutes/week in the 2 exercise groups. Attrition was 9%. Primary analyses will be intent-to-treat of intervention effect on telomere shortening. The primary endpoint will be changes in relative telomere length of leukocyte DNA. Additional analyses will be correlational, investigating associations between telomere length and other analytes already measured in the trial: DNA damage repair (COMET), sex hormones, insulin & glucose, inflammation (C-reactive protein, serum amyloid A, interleukin-6), insulin like growth factor 1 and binding protein 3, and adipokines (adiponectin, leptin). Effect modification by gene SNP alleles related to telomere length (TERT, TRF1, TNKS1, TRF2, RAP1, POT1, and rs12696304 near TERC) will also be tested. The proposed research is highly novel, and takes advantage of an existing resource of stored DNA from a completed trial. If weight loss or exercise reduces telomere shortening, it will provide additional clues to the links between these lifestyle factors and risks for cancer and other chronic diseases that have been associated with telomere length. PUBLIC HEALTH RELEVANCE: This project will investigate the effects of physical activity, reduced-calorie weight loss and the combination of these two interventions, on the length of telomeres, which is a part of DNA. Shorter telomeres have been linked to cancer risk. The project includes 438 postmenopausal, overweight/obese, sedentary women who have already completed the trial from which blood samples will be used.